Why Only Some People are Vulnerable to Life-Threatening Dengue Infections

Dengue fever, also known as "breakbone fever" for the intense aches it causes,
is transmitted by mosquitoes in the tropics and subtropics.

For most people who contract it, dengue fever is a relatively
mild-mannered disease - at least the first time around. For some,
however, a subsequent infection by the virus unleashes a vicious and
potentially deadly illness.

New research from a team based at The Rockefeller University has
begun to reveal why certain people are more vulnerable to these
dangerous secondary infections. Their latest findings, described in Science, could lead to better strategies to identify and better treat those most at risk.

‘Patients with severe secondary dengue infection have high levels of a particular type of antibody that triggers a forceful immune response.’

"Patients with severe secondary disease have high levels of a
particular type of antibody that triggers a forceful immune response.
This distinctive signature did not show up in patients with more mild
illness," says senior author Jeffrey V. Ravetch, Theresa and Eugene M. Lang Professor and head of the Leonard Wagner Laboratory of Molecular Genetics and Immunology.

"Our work sheds new light on the way in which the dengue virus
co-opts antibodies produced as a result of the previous infection, using
them to inflict more damage the second time around," Ravetch adds.

Uncommon, but dangerous

In the more
severe form of the disease, which typically occurs among people who have
been infected before, patients can develop hemorrhagic fever, which
causes them to leak fluid from their blood vessels and bleed abnormally,
sometimes from the nose, gums, and under the skin. In extreme cases,
people lose so much blood that they develop a critical condition known
as shock.

Researchers have long thought this happens because, when it infects a
second time, the virus somehow takes advantage of antibodies the immune
system is still producing as a result of the first infection. But this
doesn't explain why less than 15 of percent people who catch dengue for
the second time develop full-blown hemorrhagic fever or shock.

Previous work in Ravetch's lab suggested differences in antibodies might account for
why only some develop severe secondary infections. These Y-shaped
proteins help the body defend itself against viruses and other intruders
by latching onto infected cells with their arms. Meanwhile, their
stems, known as Fc regions, bind to immune cells and tell them how to
respond. Ravetch's lab has shown that the structure of the Fc region can
influence an immune response by, for example, promoting inflammation
versus calming it.

An answer in architecture

For the current study, first author Taia Wang, then a postdoc in the
lab, and her collaborators took a close look at the Fc regions of
antibodies in blood collected from patients with mild and severe
secondary dengue infections at Siriraj Hospital in Bangkok, Thailand.
These people's immune systems were still producing antibodies as a
result of their first encounter with the virus, but the structure of
these antibodies varied between individuals.

The researchers found that the dengue patients with more serious
disease had high levels of antibodies whose Fc regions lack a particular
sugar, a variation known to strongly activate immune cells.

In experiments, the researchers showed that activating signals from
these antibodies aggravated the disease by leading to the destruction of
blood-clotting cells called platelets. When their platelet levels
plummet, patients bleed abnormally - a hallmark of hemorrhagic fever. The
lower a patient's platelet count, the more of these distinctive
antibodies he or she tended to have.

"We found that some people's immune systems respond to dengue
infection by producing elevated levels of these pathogenic antibodies,
which make them more vulnerable to a severe secondary dengue infection,"
says Wang, who is now an assistant professor at Stanford School of
Medicine. "It's not yet clear if they produce more of these highly
activating antibodies even before they encounter the virus."

Dengue and beyond

The discovery of this antibody signature could help fight the disease in a number of ways.

"Because we now know what to look for, it may become possible to
identify patients at risk of severe illness, so they can receive
intensive, supportive care early on," Ravetch says.

"It could also aid in the development of safe dengue vaccines that
stimulate the immune system without triggering a secondary, potentially
harmful response, and of new drugs designed to help patients recover by
blocking the antibody signaling," he adds.

Since dengue belongs to the same family as Zika and other dangerous
viruses, the implications go beyond this particular disease. "It will be
important to consider the possibility that other, related viruses
employ a similar strategy, and that infection with one may affect the
subsequent response to another," he says.

Gastrointestinal Bleeding refers to hemorrhage that occurs from one or more portions of the digestive tract (that extends from the mouth to the anus). Bleeding can range from mild to severe and life threatening.

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